Volume 5, Issue 2

Background and aims Chronic visceral pain is common both in patients with identifiable organic disease and also in those without any structural, biochemical or immunological abnormality such as in the functional gastrointestinal disorders (FGIDs). We aim to provide a contemporaneous summary of pathways involved in visceral nociception and how a variety of mechanisms may influence an individual’s experience of visceral pain. Methods In this narrative review, we have brought together evidence through a detailed search of Medline in addition to using our experience and exposure to recent research developments from ourselves and other research groups. Results FGIDs are a heterogeneous group of disorders whose aetiology largely remains an enigma. The germane hypothesis for the genesis and maintenance of chronic visceral pain in FGIDs is the concept of visceral hypersensitivity. A number of peripheral and central mechanisms have been proposed to account for this epiphenomenon. In the periphery, inflammatory mediators activate and sensitize nociceptive afferent nerves by reducing their transduction thresholds and by inducing the expression and recruitment of hitherto silent nociceptors culminating in an increase in pain sensitivity at the site of injury known as primary hyperalgesia. Centrally, secondary hyperalgesia, defined as an increase in pain sensitivity in anatomically distinct sites, occurs at the level of the spinal dorsal horn. Moreover, the stress responsive physiological systems, genetic and psychological factors may modulate the experience of visceral pain. We also address some novel aetiological concepts in FGIDs, namely the gastrointestinal microbiota, connective tissue abnormalities and the gastrointestinal neuromuscular disorders. Firstly, the gastrointestinal microbiota is a diverse and dynamic ecosystem, that safeguards the host from external pathogens, aids in the metabolism of polysaccharides and lipids, modulates intestinal motility, in addition to modulating visceral perception. Secondly, connective tissue disorders, which traditionally have been considered to be confined largely to the musculoskeletal system, have an increasing evidence base demonstrating the presence of visceral manifestations. Since the sensorimotor apparatus of the GI tract is embedded within connective tissue it should not be surprising that such disorder may result in visceral pain and abnormal gut motility. Thirdly, gastrointestinal neuromuscular diseases refer to a heterogeneous group of disorders in which symptoms arise from impaired GI motor activity often manifesting as abnormal transit with or without radiological evidence of transient or persistent dilation of the viscera. Although a number of these are readily recognizable, such as achalasia or Hirschsprung’s disease, the cause in a number of patients is not. An international working group has recently addressed this “gap”, providing a comprehensive morphologically based diagnostic criteria. Conclusions/implications Although marked advances have been made in understanding the mechanisms that contribute to the development and maintenance of visceral pain, many interventions have failed to produce tangible improvement in patient outcomes. In the last part of this review we highlight an emerging approach that has allowed the definition and delineation of temporally stable visceral pain clusters, which may improve participant homogeneity in future studies, potentially facilitate stratification of treatment in FGID and lead to improvements in diagnostic criteria and outcomes.

Objective No single drug is broadly efficacious in the long-term treatment of fibromyalgia syndrome (FMS). Spironolactone is known to ameliorate mood and tension headache or migraine in women with premenstrual syndrome or clinical signs of hyperandrogenism. In a case series of women with treatment resistant FMS spironolactone was therefore added to their medication, and they were observed for at least 12 months. Methods 31 women with treatment-resistant FMS received spironolactone as add-on medication to various pain modulating drugs. 15 women responded to spironolactone and baseline data were compared with assessments over 12–14 months on treatment with spironolactone (ALDACTONE®) in dose range 100–200 mg/day. The efficacy was evaluated by the fibromyalgia impact questionnaire (FIQ) total score and 8 FIQ subtests, a German mood inventory (BSKE-EWL), and further assessments of changes in relevant psychological and physical complaints. 16 women had no effect and stopped the treatment early. Results The subsequent data refer to the 15 responders. The FIQ total score (maximal score = 80) decreased from 56.6 ± 10.0 at baseline to 17.1 ± 11.9 (mean ± SD) 12–14 months later, and pain intensity on an 11 point numeric rating scale (NRS) decreased from 8.8 ± 1.6 to 2.6 ± 1.9 (mean ± SD). Similar changes in FIQ subscores were found for fatigue, morning tiredness, stiffness, anxiety, and depression. Emotional functioning consistently improved: positive mood from 20.0 ± 5.4 to 37.7 ± 5.4 (maximal score = 48), and negative mood from 35.4 ± 5.3 to 10.0 ± 4.4 (maximal score = 60) (each mean ± SD) as well as other mental and physical dysfunctions including non-restorative sleep. All these changes at 4–6 weeks remained on this level for 11–13 months. The drug was well-tolerated and safe, no serious adverse effects were observed. Regular monitoring of serum potassium did not reveal hyperkalemia. All 15 women were able to reduce or discontinue concomitant drugs. Conclusion Fifteen of 31 women with otherwise treatment-resistant FMS experienced a number of prolonged beneficial effects from spironolactone on their complex pain-condition. Implications and discussion We hypothesise that spironolactone affects several central and peripheral neurotransmitter systems such as γ-aminobutyric acid (GABA) activity and dopaminergic transmission. The high rate of non-responsive patients underlines that FMS may represent several subgroups. Pain relief and improvement of associated FHS-symptoms and positive effects on additional diseases or dysfunctions give reasons for marked and sustained improvement in the quality of life. Well-controlled, double-blind, and randomised trials are necessary to confirm our potentially very important observations.

Background and aim Strong opioids including oxycodone are amongst the most effective analgesics to combat moderate to severe pain of various aetiologies, but opioid-induced bowel dysfunction (OIBD) represents a relevant problem. The rationale for development of a prolonged-release (PR) fixed combination of oxycodone and naloxone was to counteract OIBD. Due to its negligible oral bioavailability, the μ-opioid receptor antagonist naloxone is able to selectively displace opioids from local μ-receptors in the gastrointestinal tract without affecting central opioid binding sites. Pivotal trials of PR oxycodone/naloxone not only demonstrated improved bowel function but also equivalent analgesic efficacy compared to PR oxycodone alone. Controlled clinical trials comparing PR oxycodone/naloxone with strong opioids other than oxycodone are not available. The present study is the first data set aimed at comparing pain control, bowel function, and quality of life (QoL) in patients newly treated with or switched to PR oxycodone/naloxone or other strong opioids during routine clinical practice. Methods In this three-arm, prospective observational study, 588 patients with moderate to severe pain of varying aetiologies received either PR oxycodone/naloxone (OXN group and OXN 40/20 group with indicated use of the 40 mg/20 mg dose strength at baseline) or other strong opioids (control group), dosed according to pain severity, for 4–6 weeks. Data documented include pain intensity (NRS), bowel function (Bowel Function Index, BFI), pain-related functional impairment (BPI-SF), QoL (EuroQol EQ-5D-3L), and a global assessment of treatment. Results Patients receiving PR oxycodone/naloxone experienced a clinically important reduction in pain intensity and pain-related functional impairment of approximately 40%. The reductions of pain intensity (−2.9 ± 2.3) and pain-related functional impairment (−2.4 ± 2.3) in the OXN group were significantly more pronounced than in the control group (−2.1 ± 2.1 and −1.8 ± 1.7). In the control group, mean reductions in pain intensity did not reach the threshold of ≥30% for at least moderate clinically important differences, although patients were prescribed higher doses of morphine equivalents than OXN group patients. Improvements in bowel function (OXN: −16.0 ± 27.6; control: 3.1 ± 24.4) and QoL (OXN: 20.8 ± 24.2; control: 13.2 ± 23.1) were also significantly more pronounced in the OXN group, with BFI scores reduced to a level that reflects normal bowel function. Results for the OXN 40/20 group receiving higher doses of PR oxycodone/naloxone were in line with those for the OXN group. In the control group, more frequent gastrointestinal adverse events and less favourable ratings of tolerability resulted in a higher rate of treatment discontinuations due to adverse events. Conclusions In patients receiving PR oxycodone/naloxone, more favourable outcomes compared with other strong opioids regarding pain control, bowel function, and QoL were observed. Implications The present findings underline the value of PR oxycodone/naloxone in the management of patients with moderate to severe chronic pain. The data set further adds to our understanding of the benefits and risks of opioid treatment in routine clinical practice.

Background and aims In functional chest pain (FCP) of presumed esophageal origin central nervous system hyperexcitability is generally believed to play an important role in pain pathogenesis. However, this theory has recently been challenged. Using magnetic resonance diffusion tensor imaging, the aim was to characterize any microstructural reorganization of the pain neuromatrix in FCP patients. Methods 13 FCP patients and 20 matched healthy controls were studied in a 3T MR scanner. Inclusion criteria were relevant chest pain, normal coronary angiogram and normal upper gastrointestinal evaluation. Apparent diffusion coefficient (ADC) (i.e. mean diffusivity of water) and fractional anisotropy (FA) (i.e. directionality of water diffusion as a measure of fiber organization) values were assessed in the secondary sensory cortex, cingulate cortex, insula, prefrontal cortex, and amygdala. Results Overall, including all regions, no difference in ADC and FA values was found between the patients and controls ( P = 0.79 and P = 0.23, respectively). Post-hoc tests revealed no difference in ADC and FA values of the individual regions. However, a trend of patients having increased ADC in the mid insula grey matter and increased FA in the mid insula white matter was observed (both P = 0.065). Conclusions This explorative study suggests that microstructural reorganization of the central pain neuromatrix may not be present in well-characterized FCP patients. Implications This finding, together with recent neurophysiologal evidence, challenges the theory of visceral hypersensitivity due to changes in the central nervous system in FCP patients.

Background and purpose Female chronic pelvic pain is a significant clinical problem that burdens the health care services and work productivity, and leads to disability and reduced quality of life among the women affected. A recent systematic review reported worldwide prevalence rates for female chronic pelvic pain ranging from 2.1% to 24%. Our aim was to assess the prevalence, characteristics, and factors associated with chronic pelvic pain among women living in Denmark, and to compare these findings with a pain-free reference group. Secondly, we evaluated the impact of pain on daily life in women suffering from chronic pelvic pain. Methods A cross-sectional postal survey of the prevalence of chronic pelvic pain was undertaken in a randomly selected general female population in Denmark ( N = 2500). Inclusion criteria were: (a) ≥18 years of age and (b) living in the Capital region or the region of Zealand in Denmark. Statistical analyses included prevalence percentage rates, chi-square tests, Mann–Whitney tests, and unpaired T -tests. Logistic regression analysis was used to identify the significant independent variables and to estimate their simultaneous impact on chronic pelvic pain. The results were expressed as odds ratio and 95% confidence intervals. All tests were two-tailed and significance levels were set at p < 0.05. Results 1179 (48%) women living in representative areas of Denmark responded. The prevalence of chronic pelvic pain was 11% ( n = 130) in women ≥18 years with a prevalence of 13.6% ( n = 87) in women of reproductive age; 6.2% ( n = 73) women experienced at least moderate average pain intensity (numerical rating scale ≥4). Self-reported diagnosis of irritable bowel syndrome (20%), bladder pain syndrome/interstitial cystitis (3%), vulvodynia (9%), endometriosis (8%), and pelvic surgery in the preceding 6 months (5%) were more prevalent in cases compared to pain-free reference subjects ( p = 0.00). Chronic pelvic pain interfered with daily life “all the time” in 5% of the women, “sometimes” in 72.3%, and “not at all” in 22.7%. Factors independently associated with chronic pelvic pain were age, country of birth, and former pelvic trauma or pelvic surgery ( p < 0.05). No association was found between chronic pelvic pain and selected socio-demographic factors (residential area, educational level, cohabitation status and employment status). Conclusions Female chronic pelvic pain appears highly prevalent (11%) in Denmark (6.2% with moderate to severe pain). Women of reproductive age had a slightly increased prevalence (13.6%). Although the reported prevalence is based on 48% ( N = 1179) of the invited sample, dropout analyses found that respondents did not deviate from non-respondents. Therefore, we considered the reported prevalence rate representative for the total sample and generalisable to the general female population in Denmark. This study was cross-sectional, and relied on association-based analyses. Consequently, causality between age groups, country of birth, former pelvic surgeries and pelvic traumas and experiences of chronic pelvic pain remains unknown. Implications In order to improve prevention and treatment of chronic pelvic pain in Denmark, high quality, population-based cohort studies and randomised clinical trials are essential. The demand for trustworthy chronic pelvic pain prevalence estimates might also inspire political attention and hereby facilitate funding for further development of treatment and research.

Background Multiple chemical sensitivity (MCS) is a chronic, disabling condition characterized by recurrent multisystem symptoms triggered by common airborne chemicals. Evidence points towards abnormal sensory processing in the central nervous system (CNS) as a likely pathophysiological mechanism. No effective treatment has yet been reported, but clinical observations suggest that as pulsed electromagnetic fields (PEMF) is a treatment for some CNS disorders (depression and chronic pain), it may also be a treatment modality for MCS. Methods In an open case study, the effects of PEMF were assessed in three MCS patients. All cases received 30 min daily treatment 5 days a week for 8 consecutive weeks. Symptoms and functional impairments related to MCS, depressive symptoms, and capsaicin-induced secondary punctate hyperalgesia were assessed at baseline and weekly until an 18-week follow-up. Results Two of the three cases showed considerable improvement on all measures of symptoms and functional impairments related to MCS in response to PEMF therapy. One case showed no improvement and during the treatment period was unexpectedly diagnosed with depression. Conclusion Our findings indicate potential benefits of PEMF therapy in MCS. Implication The therapeutic effect of PEMF in MCS needs to be investigated by a randomized placebo-controlled trial.

Background and purpose Conventional neurophysiological techniques do not assess the function of nociceptive pathways and are inadequate to detect abnormalities in patients with small-fiber damage. This overview aims to give an update on the methods and techniques used to assess small fiber (Aδ- and C-fibers) function using evoked potentials in research and clinical settings. Methods Noxious radiant or contact heat allows the recording of heat-evoked brain potentials commonly referred to as laser evoked potentials (LEPs) and contact heat-evoked potentials (CHEPs). Both methods reliably assess the loss of Aδ-fiber function by means of reduced amplitude and increased latency of late responses, whereas other methods have been developed to record ultra-late C-fiber-related potentials. Methodological considerations with the use of LEPs and CHEPs include fixed versus variable stimulation site, application pressure, and attentional factors. While the amplitude of LEPs and CHEPs often correlates with the reported intensity of the stimulation, these factors may also be dissociated. It is suggested that the magnitude of the response may be related to the saliency of the noxious stimulus (the ability of the stimulus to stand out from the background) rather than the pain perception. Results LEPs and CHEPs are increasingly used as objective laboratory tests to assess the pathways mediating thermal pain, but new methods have recently been developed to evaluate other small-fiber pathways. Pain-related electrically evoked potentials with a low-intensity electrical simulation have been proposed as an alternative method to selectively activate Aδ-nociceptors. A new technique using a flat tip mechanical stimulator has been shown to elicit brain potentials following activation of Type I A mechano-heat (AMH) fibers. These pinprick-evoked potentials (PEP) have a morphology resembling those of heat-evoked potentials following activation of Type II AMH fibers, but with a shorter latency. Cool-evoked potentials can be used for recording the non-nociceptive pathways for cooling. At present, the use of cool-evoked potentials is still in the experimental state. Contact thermodes designed to generate steep heat ramps may be programmed differently to generate cool ramps from a baseline of 35 ◦ C down to 32 ◦ C or 30 ◦ C. Small-fiber evoked potentials are valuable tools for assessment of small-fiber function in sensory neuropathy, central nervous system lesion, and for the diagnosis of neuropathic pain. Recent studies suggest that both CHEPs and pinprick-evoked potentials may also be convenient tools to assess sensitization of the nociceptive system. Conclusions In future studies, small-fiber evoked potentials may also be used in studies that aim to understand pain mechanisms including different neuropathic pain phenotypes, such as cold- or touch-evoked allodynia, and to identify predictors of response to pharmacological pain treatment. Implications Future studies are needed for some of the newly developed methods.

Background A great proportion of the variation in pain experience and chronicity is caused by heritable factors. Within the last decades several candidate genes have been discovered either increasing or decreasing pain sensitivity or the risk of chronic pain in humans. One of the most studied genes is the GCH1 gene coding for the enzyme GTP cyclohydrolase 1 (GCH1). GCH1 catalyses the initial and rate-limiting step in the biosynthesis of tetrahydrobiopterin (BH4). The main function of BH4 is regulation of monoamine and nitric oxide biosynthesis, all involved in nociceptive signalling. Methods In this topical review we focus on the implication of the GCH1 gene and BH4 in painful conditions. We discuss experimental evidence from our group in relation to relevant research publications evaluating the BH4 pathway in pain. Studies assessing the role of GCH1 and BH4 in pain consist of human and animal studies, including DOPA-responsive dystonia (DRD) patients and hph-1 mice (a genetic mouse model of DRD) having mutations in the GCH1 gene as well as preclinical studies with the GCH1 inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP). The hypothesis is that genetic and pharmacological reduction of GCH1 would result in lower pain sensitivity. Results Previous studies have demonstrated that a particular “pain protective” GCH1 haplotype, found in 15% of the general human population, is linked to decreased pain sensitivity. We further support these findings in DRD patients, showing normal thresholds to mechanical and thermal stimuli, whereas a trend towards lower pain sensitivity is seen following chemical pain sensitisation. Consistent with these observations, non-injured hph-1 mice displayed normal mechano- and thermosensation compared to wild-type mice. After peripheral inflammation with Complete Freund’ Adjuvant or sensitisation with capsaicin the mutant mice exhibited lower sensitivity to mechanical and heat stimuli. Moreover, hph-1 mice showed decreased nociception in the first phase of the formalin test. Several studies report analgesic effects of GCH1 inhibition with 90–270 mg/kg DAHP in rat models of inflammatory and neuropathic pain. However, we could not completely replicate these findings in mice. Fairly higher doses of DAHP (≥270 mg/kg) were needed to reduce inflammatory pain in mice, but the window between antinociception and toxic effects was small, since 400 mg/kg DAHP affected motor performance and general appearance. Also, the analgesic effects were marginal in mice compared to that observed in rats. Conclusions Variations in the GCH1 gene in both humans and mice appear to regulate pain sensitivity and pain behaviours, particularly after pain sensitisation, whereas pain sensitivity to phasic mechanical and thermal stimuli is normal. Moreover, pharmacological inhibition of GCH1 shows antinociceptive effects in preclinical pain studies, though our studies imply that GCH1 inhibition may have a small therapeutic index. Implications The implication of the GCH1 gene in pain may increase our understanding of the risk factors of chronic pain development and improve current pain therapy by personalised medicine. In addition, inhibition of GCH1 provides a potential target for analgesic drug development, though GCH1 inhibitors should possess local or partial effects to avoid serious side-effects to the central nervous system and cardiovascular system.

Background and objective Chronic pain is a growing phenomenon worldwide. It is considered a medical problem because, besides the socio-economic issues involved, pain is often accompanied by psychosocial problems. Apart from the physical pain, living with chronic pain has many additional consequences. People living with chronic pain generally suffer from other physical and psychological consequences. The impact of chronic pain varies enormously between individuals, but the suffering is frequently pervasive and detrimental. The objective of this study was to review the evidence concerning, ways in which people living with chronic pain are affected in their everyday lives. Methods Electronic databases Scopus, Cinahl and PsycINFO were searched from 2008 to September 2012 using a ‘building blocks’ approach and reference lists were scanned. PubMed was also searched and checked for duplicates compared to Scopus, Cinahl and PsycINFO. Data were extracted from included studies and methodological quality assessed with a view to exploring quality differences. To guide the review and interpretation, individual components of methodological quality were compared against a checklist. A narrative synthesis was formulated involving three categories: (1) clinical aspects, (2) everyday life aspects and (3) interpersonal aspects. Results The search strategy identified 1140 citations; one study was found during the preliminary searching through references, and a search of reference lists provided five publications. Of these, 24 publications, representing 23 populations, met the inclusion criteria. In total, there were 22 cross-sectional studies and 2 cohort studies. Study populations ranged from 74 to 3928 participants and were heterogeneous in nature across studies with respect to age, duration and localisations of pain and outcome measures. We found a general consensus that life with chronic pain was associated with higher prevalence and higher levels of depression and diagnoses of widespread pain and nonspecific pain are more clearly associated with depression than is specific pain. The results of link between chronic pain and anxiety and stress were not obvious. Overall, there is plausible evidence to suggest a positive relationship between chronic pain and disability and the evidence is stronger for a significant positive association between nonspecific pain and disability, compared to specific pain. It can be summarized that there is a lack of evidence for a relationship between intensity of pain and quality of life. However, there is evidence that nonspecific pain is more compellingly associated with low quality of life than is specific pain. The evidence of a positive relation between pain and problems in close relations is not convincing but there is an indication to suggest that there is a pain-related issue regarding participation in many social aspects of everyday life. Conclusion Besides the pain itself, people living with chronic pain are affected in other aspects of life. In particular, it is evident that they experience challenges with respect to depressive thoughts, disability, lower quality of life and conflicts in close relationships. Implications When designing interventions for people with chronic pain, it is essential to take into consideration the fact that living with chronic pain has far-reaching consequences beyond the pain suffered.